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Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-? gene.

ABSTRACT: Peroxisome proliferator-activated receptor (PPAR)-? is a nuclear hormone receptor that is mainly involved in lipid metabolism. Recent studies have suggested that PPAR-? agonists exert vascular protective effects. The present study was designed to characterize vascular function in mice with genetic inactivation of PPAR-? in the endothelium. Mice with vascular endothelial cell-specific deletion of the PPAR-? gene (ePPAR?(-/-) mice) were generated using loxP/Cre technology. ePPAR?(-/-) mice were normotensive and did not display any sign of metabolic syndrome. Endothelium-dependent relaxations to ACh and endothelium-independent relaxations to the nitric oxide (NO) donor diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate were both significantly impaired in the aorta and carotid arteries of ePPAR?(-/-) mice (P < 0.05). In ePPAR?(-/-) mouse aortas, phosphorylation of endothelial NO synthase at Ser(1177) was significantly decreased (P < 0.05). However, basal levels of cGMP were unexpectedly increased (P < 0.05). Enzymatic activity of GTP-cyclohydrolase I and tetrahydrobiopterin levels were also enhanced in ePPAR?(-/-) mice (P < 0.05). Most notably, endothelium-specific deletion of the PPAR-? gene significantly decreased protein expressions of catalase and glutathione peroxidase 1 and resulted in increased levels of H2O2 in the aorta (P < 0.05). In contrast, superoxide anion production was unaltered. Moreover, treatment with catalase prevented the endothelial dysfunction and elevation of cGMP detected in aortas of ePPAR?(-/-) mice. The findings suggest that increased levels of cGMP caused by H2O2 impair vasodilator reactivity to endogenous and exogenous NO. We speculate that chronic elevation of H2O2 predisposes PPAR-?-deficient arteries to oxidative stress and vascular dysfunction.

SUBMITTER: d'Uscio LV

PROVIDER: S-EPMC3962632 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-δ gene.

d'Uscio Livius V LV He Tongrong T Santhanam Anantha Vijay R AV Tai Li-Jung LJ Evans Ronald M RM Katusic Zvonimir S ZS

American journal of physiology. Heart and circulatory physiology 20140131 7

Peroxisome proliferator-activated receptor (PPAR)-δ is a nuclear hormone receptor that is mainly involved in lipid metabolism. Recent studies have suggested that PPAR-δ agonists exert vascular protective effects. The present study was designed to characterize vascular function in mice with genetic inactivation of PPAR-δ in the endothelium. Mice with vascular endothelial cell-specific deletion of the PPAR-δ gene (ePPARδ(-/-) mice) were generated using loxP/Cre technology. ePPARδ(-/-) mice were no ...[more]

PMID: 24486511

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Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-? gene.

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Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-δ gene.

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